sariv2021 CCancer-Promoting fects of Microbial Dysbiosis HHS Public Access Lk Author manuscript Peer-reviewed and asoepted for publication ETE EMT Curr Oncol Rep. Author manuscript; available in PMC 2015 Oct 4 PMCID: PMc4180221 Published in final edited form as: NIHMSID: NIHMS621515 Pup: 25123079 Cancer-Promoting Effects of Microbial Dysbiosis Amy M. Shefin,’ Alyssa K. Whitney,” and Tiffany L. Weit!* ‘Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO 80523 2Department of Biology, Colorado State University, Fort Collins, CO 80523, “author to whom correspondence should be addressed: Tiffany, Welr@colostate,edu Copyright notice Abstract Humans depend upon our commensal bacteria for nutritive, immune-modulating and metabolic contributions to maintenance of health. However, this commensal community exists in careful balance that, if disrupted, enters dysbiosis; which has been shown to contribute to the etiology of colon, gastric, esophageal, pancreatic, laryngeal, breast and gallbladder carcinomas. This etiology is closely tied to host inflammation, which causes and is aggravated by microbial dysbiosis while increasing vulnerability to pathogens. Advances in sequencing technology have increased our ability to catalog microbial species associated with various cancer types across the body. However, defining microbial biomarkers as cancer predictors presents multiple challenges and existing studies identifying cancer- associated bacteria have reported inconsistent outcomes. Combining metabolites and microbiome analyses can help elucidate interactions between gut microbiota, metabolism and the host. Ultimately, understanding how gut dysbiosis impacts host response and inflammation will be critical to creating an accurate picture of the role of the microbiome in canecr. Keywords: microbiome, cancer, microbial metabolites, dysbiosis, inflammation, genotoxins Introduction The relationship between specific pathogenic bacteria and human carcinogenesis has been the subject of extensive investigation, Historically, most of this research has focused on individual pathogens, such as Helicobacter pylori, and their potential to initiate and perpetuate disease. Previous research focus ‘was on the disease process rather than beneficial gut-microbe interactions. More recently, extensive research supports commensal bacteria playing a role in protection of host health via nutritive, immune- modulating and metabolic processes [1, 2]. In addition, the more holistic approach of characterizing entire communities of gut bacteria and their interactions is now possible through use of high- throughput DNA sequencing technology. Characterization of the gut microbiome as a whole has, furthered our understanding of intestinal microbial ecology to include community-level functions and changes. In healthy individuals, the gut microbiome functions as a symbiont that can offer protection from invading pathogens and prevent tumorigenesis [3]. However, this commensal community exists in careful balance that, if disrupted, enters dysbiosis and contributes to host disease processes, including ‘cancer [4-7]. While recent findings still support individual microorganisms influencing carcinogenesis, hitpsiwowcnebl nim, nin govipmelartles/PMC#180221/ wesariv2021 Ccance-Promating Etfects of Mlabal Dysbisis greater emphasis is on microbial dysbiosis and its larger role in cancer initiation and progression. The focus of this review is on gut microbial community dynamics that shift state from symbiosis to dysbiosis and the subsequent host immune and pathogen response, which drastically alters initiation and progression of multiple types of cancer. Proposed mechanisms for microbiome involvement in colorectal cancer Multiple studies report different gut microbiome composition in individuals diagnosed with colorectal cancer (CRC) versus healthy individuals [8-11]. In fact, gut microbiota can play a role in either promotion or prevention of CRC, often through modulation of the inflammatory process due to close contact with host colonic mucosa [5]. For example, chemically induced injury and proliferation induced by azoxymethane (AOM) and dextran sulfate sodium (DSS) was enhanced in germ free mice, which lack protective commensals. In addition, tumor development in the germ-free mice resulted in significantly more and larger tumors compared to specific pathogen free mice [12]. Balance of the gut microbial community, or eubiosis, can be disrupted by an inflammatory environment in the host. For example, host inflammation may influence microbiota composition through generation of specific metabolites such as nitric oxide synthase (NOS2), Nitrate provides a unique energy source for facultative anaerobic bacteria allowing them to outcompete bacteria that cannot utilize nitrates [13], disrupting balance of the gut microbiome and resulting in dysbiosis. Pro-inflammatory responses can also compromise barrier and immune function to allow bacterial translocation through intestinal tight Junctions and intensify the inflammatory response [14] How inflammation interacts with the gut microbiome to influence CRC has been recently synthesized in several hypotheses that summarize our understanding of the interactions to date (igure 1). The “alpha-bug’ hypothesis suggests that a keystone pathogen species, such as Enterotoxigenic B. fragilis (ETBP), remodels the colonic microbiota to promote CRC, possibly via IL-17 and T}17 cell-mediated inflammation. 1 is process could also be initiated by microbial-independent host-mediated inflammation and may be blocked by beneficial commensal microbiota [15]. Similarly, the bacterial driver-passenger model suggests that ‘driver’ bacteria, such as ETBF, cause or aggravate inflammation and produce genotoxins that lead to cell proliferation and mutations. Subsequently, an adenoma forms and is colonized by ‘passenger’ bacteria such as Fusobacterium spp. that encourage tumor progression [16]. Following tumor formation, the intestinal barrier is damaged by the continual inflammation and allows bacteria access to tumor tissue. These bacteria and their metabolites stimulate additional inflammatory signals, including IL-17 eytokines, promoting cancer progression [17]. Inflammatory signals may also stimulate macrophages, via induction to an M1 phenotype, to produce chromosome- breaking factors through a bystander effect, damaging DNA and inducing chromosomal instability in neighboring cells (3). Likely CRC initiation and progression is engendered by aspects of cach of these models. hitpsiwowcnebl nim, nin govipmelartles/PMC#180221/ 26sariv2021 CCancer-Promoting Elects of Mlerblal Dysbosis, fefetefefatetel community host —_Keystone-pathogenbacleral baclenal-arver 5° JY homeostasis inflammation active yg rectuting

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